This Center is composed of five projects involving investigators at four institutions all committed to understanding the neurochemical basis of normal cognition and its dissolution in schizophrenia. Unraveling the cortical mechanisms which mediate the complex cognitive functions of the prefrontal cortex is considered an essential step in achieving this understanding. This Center is unified by the hypothesis that neurotransmitter dysregulation may produce compromised cortical architecture ("reduced neuropil") and is a primary feature of cortical functional disturbance in particularly dopamine (DA), in the regulation of excitatory neurotransmission in the circuitry of working memory. Project 1 examines the role of dopaminergic (and serotonergic) modulation of NMDA and non-NMDA receptors in working memory circuits in vivo. Project 2 introduces a potentially powerful new approach to neuropathology, the fixed-slice preparation to study dendritic morphology and cortical circuitry involving dopamine (and serotonin) in postmortem brain and a "living-then-fixed" preparation to test the hypothesis that dopamine alters dendritic morphology in prefrontal regions of non-human primate models of DA dysregulation produced in Project 3. Project 3 involves the study of non-human primate models produced by chronic (and acute)PCP and chronic AMPH sensitization which our findings indicate result in DA dysregulation; working memory, smooth pursuit eye tracking and neurochemical effects of chronic treatments will be investigated. Project 4 examines the degree of DA dysregulation in schizophrenia by measuring DA turnover and D2 receptor density in cortex and the striatum of schizophrenic patients using SPECT imaging to test the hypothesis that low basal levels of DA predispose to high phasic response. Project 5 is a coordinated study in normal monkeys, normal humans and patients with schizophrenia designed to test the novel hypothesis that reduction in glutamatergic neurotransmission has therapeutic potential in the treatment of schizophrenia. The collective results from these projects will illuminate our understanding of the interactions between DA and its cellular and subcellular targets in prefrontal cortex and establish the role of dopamine dysregulation in the etiology, pathophysiology, and neuropathology of schizophrenia.